The absence of serum complement antiviral activity seen in lentiviral diseases of humans and animals, and the genus-species specificity were the major initiatives in this project. A systematic analysis for anti-human immunodeficiency virus (HIV) inactivating activity of sera from various members of the animal kingdom was performed. Sera from the rodent and feline families were the most potent inhibitors of HIV infection in vitro. The serum factor(s) was heat-labile, 56 degrees C for 30 minutes, completely dependent on Ca++ as demonstrated by EDTA inhibition and independent of antibody. The sera were capable of inactivating, in a dose-- dependent fashion, all strains of HIV-1 and HIV-2 tested. Preliminary studies suggest the activity does not require complement components beyond C5. Characterization is ongoing in attempts to understand its mechanism of action for application to the human acquired immunodeficiency syndrome condition. Side-chain derivatized CD4 (81-92) peptides inhibit HIV-induced cell fusion and HIV-1 infection of susceptible cells in vitro at micromolar concentrations. Peptide potency to block HIV infection/fusion is paralleled by potency to block gpl2O binding to CD4 in both cell and cell free binding assays. Cyclic derivatives of these peptides are more potent than their open-chain congeners. Extension of peptides by eight amino acids into the CDR-3-homologous region of CD4 eliminates the need for multiple derivatization of the molecule. Data support the hypothesis that CD4 (81-92) derived peptides inhibit HIV-1 and simian immunodeficiency virus infectivity and cytopathic effect by mimicking the region of CD4 that binds gpl2O, and acting as a competitive "antireceptor" for the binding of the gpl2O to cell-surface CD4. Several anti-CD4 monoclonal antibodies bind to CDR-3-derived peptides and inhibit HIV-1 infection as well as HIV-1-induced cell fusion, thus providing further support for the primary involvement of the CDR-3-homologous domain of CD4 in binding to gpl2O. CD4 (81-92) is capable of blocking HIV-1 at several stages of its viral life cycle.